A statistical experimental design approach to evaluate the influence of various penetration enhancers on transdermal drug delivery of buprenorphine

A series of drug-in-adhesive transdermal drug delivery systems (patch) with different chemical penetration enhancers were designed to deliver drug through the skin as a site of application. The objective of our effort was to study the influence of various chemical penetration enhancers on skin permeation rate and adhesion properties of a transdermal drug delivery system using Box–Behnken experimental design. The response surface methodology based on a three-level, three-variable Box–Behnken design was used to evaluate the interactive effects on dependent variables including, the rate of skin permeation and adhesion properties, namely peel strength and tack value. Levulinic acid, lauryl alcohol, and Tween 80 were used as penetration enhancers (patch formulations, containing 0–8% of each chemical penetration enhancer). Buprenorphine was used as a model penetrant drug. The results showed that incorporation of 20% chemical penetration enhancer into the mixture led to maximum skin permeation flux of buprenorphine from abdominal rat skin while the adhesion properties decreased. Also that skin flux in presence of levulinic acid (1.594 lg/cm2 h) was higher than Tween 80 (1.473 lg/cm2 h) and lauryl alcohol (0.843 lg/cm2 h), and in mixing these enhancers together, an additional effect was observed. Moreover, it was found that each enhancer increased the tack value, while levulinic acid and lauryl alcohol improved the peel strength but Tween 80 reduced it. These findings indicated that the best chemical skin penetration enhancer for buprenorphine patch was levulinic acid. Among the designed formulations, the one which contained 12% (wt/wt) enhancers exhibited the highest efficiency.

Journal of Advanced Research (2015) 6, 155–162 Cairo University Journal of Advanced Research ORIGINAL ARTICLE A statistical experimental design approach to evaluate the influence of various penetration enhancers on transdermal drug delivery of buprenorphine S.Mojtaba Taghizadeh *, Ali Moghimi-Ardakani, Fatemeh Mohamadnia Department of Novel Drug Delivery Systems, Science Faculty, Iran Polymer and Petrochemical Institute, Tehran, Iran A R T I C L E I N F O Article history: Received 27 September 2013 Received in revised form 25 December 2013 Accepted 12 January 2014 Available online 20 January 2014 Keywords: Buprenorphine Transdermal Box–Behnken design Skin penetration enhancer Adhesion A B S T R A C T A series of drug-in-adhesive transdermal drug delivery systems (patch) with different chemical penetration enhancers were designed to deliver drug through the skin as a site of application The objective of our effort was to study the influence of various chemical penetration enhancers on skin permeation rate and adhesion properties of a transdermal drug delivery system using Box–Behnken experimental design The response surface methodology based on a three-level, three-variable Box–Behnken design was used to evaluate the interactive effects on dependent variables including, the rate of skin permeation and adhesion properties, namely peel strength and tack value Levulinic acid, lauryl alcohol, and Tween 80 were used as penetration enhancers (patch formulations, containing 0–8% of each chemical penetration enhancer) Buprenorphine was used as a model penetrant drug The results showed that incorporation of 20% chemical penetration enhancer into the mixture led to maximum skin permeation flux of buprenorphine from abdominal rat skin while the adhesion properties decreased Also that skin flux in presence of levulinic acid (1.594 lg/cm2 h) was higher than Tween 80 (1.473 lg/cm2 h) and lauryl alcohol (0.843 lg/cm2 h), and in mixing these enhancers together, an additional effect was observed Moreover, it was found that each enhancer increased the tack value, while levulinic acid and lauryl alcohol improved the peel strength but Tween 80 reduced it These findings indicated that the best chemical skin penetration enhancer for buprenorphine patch was levulinic acid Among the designed formulations, the one which contained 12% (wt/wt) enhancers exhibited the highest efficiency ª 2014 Production and hosting by Elsevier B.V on behalf of Cairo University Introduction * Corresponding author Tel.: +98 21 48662496; fax: +98 21 44580192 E-mail address: S.M.taghizadeh@ippi.ac.ir (S.M Taghizadeh) Peer review under responsibility of Cairo University Production and hosting by Elsevier A recent approach in drug delivery system is administering drugs with specific rates through skin as the site of application In the past decade, much attention has been paid to a specific transdermal drug delivery system (TDD), also known as ‘‘patch’’ system [1] This system has many advantages such as the elimination of the first pass effect and its side effects with 2090-1232 ª 2014 Production and hosting by Elsevier B.V on behalf of Cairo University http://dx.doi.org/10.1016/j.jare.2014.01.006 156 steady delivery of medicine over long period of time [2] Nevertheless, this system has some limitations It is known that some agents such as penetration enhancers and pressure sensitive adhesives can have influence on skin permeation flux and adhesive properties of TDDs [3–5] Buprenorphine is a partially opiate drug with an analgesic potency of about 25–50 times higher than an equivalent dose of morphine This drug has sufficiently low molecular weight with lipophilic properties so it can be a suitable candidate to be administered by TDDs This drug has been used to relieve chronic and cancer pain via several routes such as sublingual and transdermal [6,7] TranstecÒ is a transdermal formulation of buprenorphine which has become available in three dosage levels [8] Although transdermal drug delivery has many advantages in relation to inherent barrier properties of the skin, but as yet it is not widely used Many different approaches have been adopted to overcome the barrier properties of skin, such as mechanical and chemical penetration enhancers Therefore, chemical penetration enhancers are used in TDDs to increase the diffusion rates of drugs to overcome the resistance of stratum corneum [9] Although there are some literature sources that have evaluated the effects of chemical penetration enhancers on skin permeation flux and mode of behavior of different hydrophilic and hydrophobic drugs, but no report has been published yet on the role of buprenorphine with respect to skin permeation flux and adhesion properties of the final patches using an adhesive with carboxylic functionality incorporated with lauric alcohol, leuvinic acid, and a surfactant such as Tween 80, as skin penetration enhancers into the formulations In the present work, the optimization of the final desirable formulations for skin permeation flux and adhesion properties was also accomplished by Box–Behnken method as a statistical tool and that such combination has not been tried before by other researchers The objective of the present work was to design new TDDs with an acrylic adhesive and different types and concentrations of chemical penetration enhancers (CPE) and to study their skin permeation flux and adhesion properties For this purpose the best formulation was selected by employing response surface experimental design method Therefore, levulinic acid, lauryl alcohol, and Tween 80 were used as penetration enhancers as variable parameters in order to evaluate their effects on skin permeation flux and adhesion properties of their corresponding systems S.M Taghizadeh et al Determination of buprenorphine The standard and real samples of buprenorphine were analyzed by HPLC (Younglin, SDV30) with UV detector at 285 nm The HPLC separation system consisted of a PerfectSil Target C18 column (150 · 4.6 mm, lm) equipped with a guard column (10 · 4.0 mm, lm); the temperature of HPLC column was maintained at 40 °C The mobile phase consisted of acetonitrile/KH2PO4 10 mM (45:55) with pH 3.0 ± 0.1 (adjusted by phosphoric acid) at ml/min flow rate, and the volume of injection was set at 20 ll A standard stock solution of buprenorphine (1000 lg mLÀ1) was prepared in methanol Calibration standard solutions of 0.5, 1, 5, 10, 15, 20, 30 lg/ml of buprenorphine were prepared by further dilution of a stock standard solution in phosphate buffer (pH 6) All of these solutions were stored in a refrigerator (4 °C) and brought to ambient temperature just prior to use Each peak area was plotted against its corresponding concentration to obtain the calibration graph The data of peak area versus concentration were treated by linear least square regression analysis The method was validated according to the ICH guidelines [10] The validation characteristics included accuracy, precision, linearity range, selectivity, limit of detection (LOD), and limit of quantitation (LOQ) The results showed a good correlation between analyte peak area and concentration with (r2 = 0.9990) The limit of detection (LOD) and limit of quantitation (LOQ) in the release media were 0.15 and 0.5 lg mLÀ1, respectively Also, to evaluate the performance of the proposed method, it was used in the analysis of buprenorphine level in real samples Sample preparation The preparation of buprenorphine patches was performed in two stages At first, the pressure sensitive adhesive (DuroTak 87-2196) was thoroughly mixed with each chemical penetration enhancer and buprenorphine in a rotary mixer at room temperature to prepare formulations as given in Table In the next step, the mixed solutions (total weight of each solution: g) were coated on the \ cm2 backing layer (outermost layer) of the patch by an Elcometer film applicator (3580 SPRL 75 mm) to obtain a layer with uniform thickness (80 lm) Next, the prepared film was kept at ambient temperature for 20 and then placed in an oven of 50 °C for 40 to remove the remaining solvent completely [11] Skin preparation for permeation study Material and methods Materials Acrylic adhesive Duro-Tak 87-2196 was purchased from National Starch and Chemical Company, USA Tween 80 and levulinic acid (LEA) were obtained from Merck, Germany Lauryl alcohol (LA) was supplied by Fluka, USA Buprenorphine, as an active ingredient, was obtained from Behansar Pharmaceutical Company, Iran The backing layer with thickness of 85 lm and Scotchpak1022 as a release liner was provided from M Company, USA All solvents of high-performance liquid chromatography (HPLC) grades were purchased from Merck, Germany Male Sprague–Dawley rats, each weighing 250 ± 25 g, supplied by Razi Vaccine and Serum Research Institute were anesthetized with ether The abdominal hair of each rat was shaved by hand razors, and a · cm2 area of a full thickness abdominal skin was surgically removed For removal of the residual fat, the dermis section of the skin was soaked in isopropyl alcohol The skin was brought into contact with normal saline 1h before sampling from the diffusion cell [12–14] All Institutional and National Guidelines for the care and use of animals were followed Permeation study Permeation studies of buprenorphine from a drug-in-adhesive patch were performed in a well-characterized Chien diffusion Influence of skin penetration enhancers on buprenorphine patch release system Table 157 Formulation components as independent variables (wt/wt%) Run (randomly) Run (formulation number) Lauryl alcohol (wt/wt%) Tween 80 (wt/wt%) Levulinic acid (wt/wt%) Adhesive (wt/wt%) Buprenorphine content (wt/wt%) 13 10 15 11 12 14 10 11 12 13 14 15 0 4 4 4 8 0 8 4 4 4 8 4 0 4 80 72 80 88 80 80 72 80 88 88 80 80 80 80 72 8 8 8 8 8 8 8 cells with diffusion area of cm2 and kept at fixed temperature of 37 °C The receptor compartment was filled with ml phosphate buffer solution of pH as a receptor medium The prepared skin was cut by about 1.5 · 1.5 cm2 dimension and put on the receptor cell, and the transdermal patch was applied onto the stratum corneum (SC) of the skin At each predetermined time interval (1, 2, 4, 8, 12, 24, 36, 48, 56, 72 and 96 h), a definite volume (3 ml) of solution was withdrawn from the receptor compartment which was immediately compensated by an equal volume of fresh phosphate buffer Finally, the drug concentration of each sample was determined by a Younglin HPLC analyzer (SDV30) [13,15] Data analysis The skin flux of buprenorphine through the abdominal skin was calculated by plotting the cumulative amount of buprenorphine permeated through skin versus time The steady state flux and lag time were estimated from the slope of the linear region of the obtained graph and its intercept on the Xaxis, respectively [16] Scanning electron microscopy (SEM) Scanning electron microscopy (SEM) was performed on VEGA/TESCAN model operating at an accelerating voltage of 20 kV and magnification of 10,000· The specimens were cryogenically fractured in liquid nitrogen and coated by a thin layer of gold to improve resolution Probe tack test Tack tests were performed on all samples, each with 80 lm thickness, according to (ASTM D-2979), by using a Chemie Instrument Probe Tack-500 (Fair Field, Ohio, USA) for at least five samples [13] Peel strength measurement at 180° Peel tests on adhesive-coated tapes were carried out according to ASTM D-3330 [13] The samples, each 2.5 · 2.5 cm2, were adhered to a stainless steel as a test panel and then rolled twice with a 4.5 kg roller to bond it to the test panel firmly The tests were measured at a peel rate of 300 mm/min by using a Chemie Instrument adhesive/release tester AR-1000 (Fair Field, Ohio, USA) The test was repeated at least five times on identical samples Thermal analysis The glass transition temperature (Tg) of various formulations was measured by differential scanning calorimeter (DSC) on a PL-1500 with heating rate of 10 °C/min under N2 atmosphere It should be noted that exactly the same sample preparation steps, given in sample preparation method, were adopted for all samples except with different coating Each test sample was coated on the release liner while the main sample was coated on the backing layer The reason of such action was that at the time of testing, the coated layer needed to be separated from release liner for conducting such test Experimental design The Design-Expert 6.0.0 software of response surface method was used to estimate the coefficient of model for statistical design of the experiments [17] A response surface methodology (RSM) using Box–Behnken design, with three factors and three levels, was performed to investigate the effect of variable factors on system’s response Some factors in the analysis of variance table such as prediction of multiple correlation coefficients (prediction R2), adjusted R2, lack of fit, and P-value were important for selection of adequate models [18,19] The modified quadratic was selected as a good fit for model The concentration effects of levulinic acid (LEV), lauryl alcohol (LA), and Tween 80 (T), as independent variables, on skin permeation, tack value, and peel strength were investigated In Box–Behnken design, the experimental points were placed on a hypersphere with some characteristics as follows:  Number of experiments obtained from N = k (k À 1) + Cp where k would be the number of factors and Cp the number of central points  All factor levels adopted at three levels 158 S.M Taghizadeh et al A number of 15 experiments were obtained with three factors and three levels, and they were augmented with three replications at the central point to estimate ‘‘pure error.’’ A polynomial model, to include interactions and quadratic terms, was adopted as follows: Y ẳ b0 ỵ k k k X k X X X bi xi ỵ bii x2ii ỵ bij xi xj ỵ e iẳ1 iẳ1 tively This meant that the model equation achieved from RSM was suitable to depict the skin permeation ux under 1ị iẳ1 i6jj where Y denoting the response; k as the number of variables; xi symbolizing the independent variables; e the residual associated to the experiments; b0 the constant of coefficient; and bi, bii, and bij representing the coefficients of the linear, quadratic, and interaction parameters, in the order given For Box–Behnken model, with three variable factors and three levels (k = 3), the Eq (1) was expanded as follows [17,19,20] Y ẳ b0 ỵ b1 x1 ỵ b2 x2 ỵ b3 x3 ỵ b11 x21 þ b22 x22 þ b33 x23 þ b12 x1 x2 þ b13 x1 x3 þ b23 x2 x3 Þ ð2Þ In this study, the concentrations of independent variables were adjusted as 0%, 4%, 8% (wt/wt) and also all formulations contained 8% (wt/wt) buprenorphine as given in Table The effects of independent variables on dependent variables, shown in three-dimensional plots, were obtained for responses based on the effects of three variable factors at three levels Results and discussion Skin permeation studies Skin permeation across rat skin for 15 formulations, each containing 8% (wt/wt) buprenorphine, was evaluated, and the results of permeation parameters were summarized and presented in Table The skin permeation flux and the effects of levulinic acid (LEV), lauryl alcohol (LA), and Tween 80 (T) were determined by RSM to promote an empirical model The quadratic equations for skin permeation were developed, and the ANOVA results for this model showed that the quadratic equation was no lack of fit, and the coefficient of prediction (R2) and adjusted (R2) were found to be 0.81 and 0.84, respecTable Fig Response surface for skin permeation flux versus (A) for LA and LEV at T = 4% and (B) for LA and T at LEV = 4% Skin permeation parameters Run (formulation number) Correlation coefficient Skin permeation flux (lg/cm2 h) SD Lag time (h) 10 11 12 13 14 15 No enhancer 0.994 0.991 0.972 0.996 0.991 0.996 0.988 0.996 0.990 0.995 0.995 0.991 0.995 0.984 0.969 0.971 2.026 3.087 2.544 1.594 1.341 2.344 2.669 1.445 0.843 1.473 1.851 1.282 1.672 1.681 2.865 0.572 0.5 1.01 1.001 0.23 0.02 0.8 0.8 0.12 0.01 0.1 0.7 0.3 0.2 0.86 1.53 0.6 0.81 ± 0.003 n.d a 4.27 ± 0.006 0.98 ± 0.007 2.57 ± 0.006 0.76 ± 0.001 n.d 1.36 ± 0.005 2.88 ± 0.001 1.38 ± 0.001 1.92 ± 0.006 1.26 ± 0.006 1.42 ± 0.004 3.36 ± 0.009 n.d 4.31 ± 0.003 a n.d = this value cannot be determined Influence of skin penetration enhancers on buprenorphine patch release system chemical skin penetration enhancer concentrations The final model adopted for skin permeation flux was as follows: Skin permeation flux ¼ 1:66 ỵ 0:44LAị ỵ 0:2Tị ỵ 0:53LEVị ỵ 0:39LAị2 To investigate the effects of LEV, LA and T on skin permeation of buprenorphine the response surface graphs were plotted and presented in Fig The Table is given to confirm the claim made by Fig The plots in Fig show that the skin permeation flux is enhanced with increase in LEV, LA, and T percentages in each mixture The simultaneous addition of LEV, LA, and adhesive (run 3) has had an additional effect, and hence, the skin permeation flux is increased As it is listed in Table and the coefficient of LEV(0.53) in equation of skin permeation flux, among all enhancers, the addition of LEV to the formulation (run 4) has resulted in higher skin permeation flux compared to formulations (with lauryl alcohol only) and 10 (with Tween 80 only) The effect of LA in enhancement of skin permeation flux could be due to the chemical structure of LA, because this fatty alcohol might disrupt the intercellular lipid bi-layers and increase the diffusion of the drug into the skin Besides, LA might fluidize the lipids in stratum corneum (SC) and so increase the partitioning of the drug into skin [21,22] Therefore, with increases in diffusion coefficient and partitioning of drug, the skin permeation flux might be enhanced Fig Tween 80 as a non-ionic surfactant might enhance the skin permeation flux by two possible mechanisms First, the surfactants increase the fluidity and solubility of lipid components of SC followed by their permeation into the intercellular of the SC Then, the surfactants could come into interaction and bind with keratin fibrils and possibly disrupt the corneocyte The chemical structure of Tween 80 may help the skin permeation of buprenorphine by lipophilic and hydrophilic mechanisms and therefore enhancing the partition process between the lipophilic content and hydrophilic protein [16,23,24] As it is illustrated in Table 2, among some types of additives used in this study, the formulation containing LEV shows the highest skin permeation flux so it may have acted as a chemical skin penetration enhancer The enhancement of skin permeation flux by LEV may be associated with disrupting the intercellular lipid domains [25], while Holas et al [26] have reported the important role of hydrogen bonding taking place between the permeation enhancers and the drug As our objective was to decrease the interaction between the drug and the adhesive, therefore the permeation of the drug through the skin was enhanced by LEV which might have increased skin permeation flux The results given in Table demonstrate that the simultaneous addition of LEV and LA into the mixture has boosted skin permeation flux compared to the mixture into which LEV and other enhancers have been added This is clearly evident in SEM images, where the micrographs reveal higher solubility of buprenorphine in the patch matrix (Fig 2) of LEV-LA (run SEM micrographs of (A) sample (B) sample at 10,000· magnification Fig 159 Tack value for all samples 160 S.M Taghizadeh et al 3) and LEV samples These images contain white spots which reveal the drug phase The micrographs indicate that solubility of drug in formulation (run 3) is higher than formulation (run 4) The reason for this behavior can be explained by simultaneous addition of LEV and LA into the mixture and its effect on skin permeation flux Table Glass transition temperature of samples Run (formulation number) Tg (°C) 10 No enhancer À37 À47.3 À55.7 À50.7 Studies on adhesive properties (tack value and peel strength) For prediction of tack value, a modified quadratic model was used The quadratic equations for tack have been developed as: Tack ¼ 4:65 À 0:23LAị ỵ 0:19Tị ỵ 0:39LEVị 0:51LAị2 0:71LAịTị 0:63ðLEVÞðTÞ ANOVA table illustrates that the quadratic model has no lack of fit, and adjusted R2 and prediction R2 are close to each other, and some factors such as LEV, LA \ T and T \ LEV are significant parameters, implies that P-value is less than 0.05 These results are observed, and the selected model seems adequate to show the actual relationship between the responses and significant variables Fig Response surface for tack value versus (A) for T and LEV at LA = 4% and (B) for LA and T at LEV = 4% Tack is the property of adhesives that allows the immediate formation of a bond with another surface under light contact pressure Tack is a complex response of adhesive surface and bulk properties, so viscoelastic properties and glass transition temperature of adhesive play important role in degree of tack value [27] It is worth mentioning that another sample (with no enhancer) was prepared, besides other samples mentioned in Table 1, with the following specification: LEV = 0%, LA = 0% and T = 0% (wt/wt) and designated as ‘‘no enhancer.’’ The reason for preparation of such sample was to estimate the effect of additives on adhesion properties As shown in Fig 3, by addition of each CPE to the mixture, the tack values were found to be higher than a sample having ‘‘no enhancer,’’ and this aspect is included in tack value equation It is evident that in Fig 4, all skin permeation enhancers show increased tack value by up to 12% incorporated CPE adhesive Fig Response surface for peel strength versus (A) for T and LEV at LA = 4% and (B) for LA and LEV at T = 4% Influence of skin penetration enhancers on buprenorphine patch release system Table shows glass transition temperature (Tg) of the mixtures in presence of each skin penetration enhancer As it is evident in samples containing LEV and LA of 4% (w/w) have higher Tg and Tween 80 (in 4% w/w) has lower Tg As it is illustrated in Fig 3, the tack values of all samples are higher than the sample with ‘‘no enhancer’’ and so CPE has acted as tackifier, though according to Table 3, Tween 80 has acted as a plasticizer, and LEV and LA have acted as tackifiers as well The effect of plasticizer has been reported to lower the Tg and the modulus of the compound and thus increasing the fluidity of the adhesive and wetting of the adherent [28] Therefore, the plasticizer has increased the tack value and has provided viscous flow of the adhesive for bonding with a low deformation rate On the other hand, LEV and LA which have increased the Tg of the mixture might have also enhanced the tack value due to increased G00 at higher frequency [27,29] The equation below describes the modeling of peel strength by using a quadratic model: 161 on peel strength was observed The reason for that was due to increased Tg by addition of LEV and LA Cantor et al have shown that there is a relationship between Tg and peel strength of pressure sensitive adhesive [29] In this respect, Kendall et al have reported that the peel adhesion increases with higher Tg [29] and Schrijvers et al have stated that peel and tack could be enhanced with increased Tg [29] On the other hand, Taghizadeh et al have found that the peel strength is decreased with lower Tg of the mixture [30] Tween 80 reduces Tg of the mixture by increasing the space between the entanglement and free volume so it plays the role of a plasticizer Therefore, the results have shown that peel strength is decreased by addition of Tween 80 into the mixture It should be noted that the above effects are found to be valid up to 12% CPEs incorporated into the adhesive and after that the peel strength is dropped because of the relative reduction in adhesive content Conclusions Peel strength ẳ 2:55 ỵ 0:015LAị 5:69Tị ỵ 0:3LEVị 0:82LAị2 ỵ 4:85Tị2 ỵ 0:22LEVị2 0:42LAịTị ỵ 0:4LAịLEVị 1:43TịLEVị There has been no lack of fit for this model This model has significant terms such as T, LA2, T2, and T \ LEV Therefore, P-value is below 0.05 for these terms Also, the adjusted R2 and prediction R2 were 0.98 and 0.94, respectively Thus, this model has best prediction for response It is shown in Fig that the incorporation of just LEV or LA into the mixture the peel strength would be higher than neat mixture (sample without enhancer) which may also be proved by peel strength equation as well In Table 4, the coefficients in dependent variables equation with their P-values are presented By addition of LEV and LA together into the mixture, the synergistic effect Table Coefficients of dependent variables equation with their P-values CPE Coefficient of equation P-value Skin permeation LA T LEV LA2 +0.44 +0.2 +0.53 +0.39 0.046 0.044 0.049 0.047 Tack LA T LEV LA2 (LA)(T) (LEV)(T) À0.23 +0.19 +0.39 À0.51 À0.71 À0.63 0.051 0.053 0.049 0.051 0.046 0.042 Peel strength LA T LEV LA2 T2 LEV2 (LA)(T) (LA)(LEV) (LEV)(T) +0.015 À5.69 +0.3 À0.82 +4.85 +0.22 À0.42 +0.4 À1.43 0.052 0.039 0.051 0.041 0.036 0.052 0.051 0.053 0.046 The effects of different types of chemical penetration enhancers on skin permeation flux, tack value, and peel strength of buprenorphine transdermal patches were investigated It was found that skin penetration flux of buprenorphine and adhesion properties of the patches were controlled by each permeation enhancer concentration LEV, LA, and Tween 80 could enhance permeation flux of buprenorphine through the skin Also, both LEV and LA together have had synergistic effect on skin permeation flux According to adhesion properties, it was observed that by addition of LEV, LA, and Tween 80 into the matrix, the tack value was increased due to the two former roles as tackifiers and Tween 80 acting as a plasticizer On the other hand by 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Matos G, David J, Brandao G, et al Box–Behnken design: an alternative for the optimization of analytical methods Anal Chim Acta 2007;597:179–86 [20] Hanrahan G, Lu K Application of factorial and... (wt/wt) and designated as ‘‘no enhancer.’’ The reason for preparation of such sample was to estimate the effect of additives on adhesion properties As shown in Fig 3, by addition of each CPE to the